The anti-neoplastic drug cisplatin (cis-diamminedichloroplatinum or “CDDP”), and related platinum based drugs including carboplatin and oxaliplatin, are widely used in the treatment of a variety of malignancies including, but not limited to, cancers of the ovary, lung, colon, bladder, germ cell tumors and head and neck. Platinum complexes are reported to act, in part, by aquation (i.e., to form reactive aqua species), some of which may predominate intracellularly, and subsequently form DNA intra-strand coordination chelation cross-links with purine bases, thereby cross-linking DNA. This mechanism is believed to work predominantly through intra-strand cross-links, and less commonly, through inter-strand cross-links, thereby disrupting the DNA structure and function, which is cytotoxic to cancer cells. Platinum-resistant cancer cells are resilient to the cytotoxic actions of these agents. Certain cancers exhibit intrinsic de novo natural resistance to the killing effects of platinum agents and undergo no apoptosis, necrosis or regression following initial platinum compound treatment. In contrast, other types of cancers exhibit cytotoxic sensitivity to platinum drugs, as evidenced by tumor regression following initial treatment, but subsequently develop an increasing level of platinum resistance, which is manifested as a reduced responsiveness and/or tumor growth following treatment with the platinum drug (i.e., “acquired resistance”). Accordingly, new platinum agents are continually being sought which will effectively kill tumor cells, but that are also insensitive or less susceptible to tumor-mediated drug resistance mechanisms that are observed with other platinum agents.
In attempting to solve this problem, one research group (see, Uchiyama, et al., Bull. Chem. Soc. Jpn. 54:181-85 (1981)) has developed cisplatin complexes possessing a nitrile group substituted for each of the amine groups in cisplatin (IUPAC Nomenclature: cis-bisbenzonitriledichloroplatinum(II)). The structural formula for this complex is shown below:

In general, nitrile-ligand based platinum complexes are less polar and more lipophilic (i.e., hydrophobic) than the currently-marketed platinum-based drugs, and thus can be dissolved into less polar solvents including, but not limited to, methylene dichloride, chloroform, acetone, N,N-dimethylformide, N,N-dimethylacetamide, and the like. This greater lipophilicity may allow such complexes to be taken up more readily by cancer cells, by facile diffusion/transport through the lipid bilayer of the cell membrane, than similar, currently utilized chemotherapeutic agents. The greater lipophilicity may, therefore, increase the available concentration of the platinum species that can participate in cytotoxic anti-tumor effects on the DNA within cancer cells.
Additionally, the lone pair of electrons on nitrogen in the nitrile group is located in the sp hybrid orbital, which is closer to the nitrogen nucleus than the sp3 hybrid orbital in the amine ligand. Thus, in platinum complexes, the attraction of the nitrogen nucleus in nitrile ligand for the lone pair of sharing electrons with platinum is greater than in the ammine ligand. This effect results in decreasing the ionic effect between platinum (II) and the leaving group, and increasing their covalent bonding characteristics. As a result, the leaving groups are more difficulty to displace by substitution, including aquation, and therefore slower rates of aquation are observed in nitrile N-donor platinum complexes as compared to ammine platinum complexes. It appears that both the nitrile ligand-based platinum complexes and the intermediate platinum complexes they form upon hydrolysis, possess a slower rate of reaction with naked DNA compared to ammine ligand-based platinum complexes. It is assumed that the slower rate of cross-linkage formation of platinum complexes with DNA bases may be less susceptible to tumor-mediated platinum-DNA repair mechanisms, which is one of the key platinum drug resistance mechanisms. In addition, and equally important from a pharmacological, toxicological, chemical and drug-resistance circumvention mechanistic point of view, the nitrile-, azido-, and R—N═N-containing platinum complexes described below are predicted to be substantially less chemically reactive than, e.g., cisplatin, carboplatin and oxaliplatin. Therefore, these nitrile-, azido-, and R—N═N-containing platinum complexes react substantially more slowly with, and thereby avoid unwanted platinum-sulfur and platinum-nitrogen conjugates with, the thiols, disulfides, and proteins/peptides present in vivo; specifically the sulfur-containing physiological thiols, disulfides, and peptides/amino acids, including but not limited to, glutathione, cysteine, homocysteine, methionine, and all other sulfur-containing and imidazole-containing (e.g., histidine), or arginine or lysine di- tri- and larger peptides, that participate in tumor-mediated platinum drug resistance. Therefore, these novel nitrile, azido, and other nitrogen ligand-based platinum complexes have potential to circumvent de novo and acquired tumor-mediated cisplatin resistance and kill cancer cells that possess both natural and acquired resistance to other known platinum drugs. The platinum complexes described below are also thought to permit controlled reduction of the chemical reactivity of the platinum species to such a degree that greater amounts of the platinum species are also delivered intracellularly with their original chemical entities. This improved delivery of platinum that is available for intracellular DNA adduct formation is mediated by a substantial reduction in the amount of non-effective and non-specific reactions of these novel platinum species with proteins and physiological thiols and disulfides, which can prevent or attenuate the antitumor effects of conventional platinum complexes.
The reaction for cisplatin hydrolysis is illustrated below in Scheme I:

In neutral pH (i.e., pH 7), deionized water, cisplatin hydrolyze to monoaqua/monohydroxy platinum complexes, which is less likely to further hydrolyze to diaqua complexes. However, cisplatin can readily form monoaqua and diaqua complexes by precipitation of chloro ligand with inorganic salts (e.g., silver nitrate, and the like). Also, the chloro ligands can be replaced by existing nucleophile (e.g., nitrogen and sulfur electron donors, etc.) without undergoing aquation intermediates.
Cisplatin is relatively stable in human plasma, where a high concentration of chloride prevents aquation of cisplatin. However, once cisplatin enters a tumor cell, where a much lower concentration of chloride exists, one or both of the chloro ligands of cisplatin is displaced by water to form an aqua-active intermediate form (as shown above), which in turn can react rapidly with DNA purines (i.e., Adenine and Guanine) to form stable platinum—purine—DNA adducts. One limitation associated with these bis-nitrile platinum complexes is that their DNA adducts may not be as stable as cisplatin-DNA adducts, because the ammine groups in cisplatin participate in local hydrogen bonding with the DNA structure to stabilize these DNA-platinum complexes. The lack of local hydrogen bonding interaction between the bis-nitrile platinum complexes and the DNA structure potentially decreases the binding affinity of bis-nitrile platinum complexes with DNA. Therefore, their adducts with DNA bases may be more susceptible to tumor-mediated platinum-DNA repair mechanisms. Thus, there remains a need for new, novel platinum complexes that can form more stable complexes with DNA bases (with increased binding affinity) and be readily taken up by tumor cells. These complexes may be markedly more effective against chemotherapy-resistant tumors than either cisplatin or the currently-available chemotherapeutic agents.